EP3747896A1 - Composition pharmaceutique comprenant un dérivé acylé d'analogue d'insuline humaine et son procédé de préparation - Google Patents

Composition pharmaceutique comprenant un dérivé acylé d'analogue d'insuline humaine et son procédé de préparation Download PDF

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EP3747896A1
EP3747896A1 EP19747024.8A EP19747024A EP3747896A1 EP 3747896 A1 EP3747896 A1 EP 3747896A1 EP 19747024 A EP19747024 A EP 19747024A EP 3747896 A1 EP3747896 A1 EP 3747896A1
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Prior art keywords
pharmaceutical composition
human insulin
lysine
integer
insulin analog
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German (de)
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EP3747896A4 (fr
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Xiaorong YANG
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/62—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an acylated derivative of human insulin analog and a preparation method thereof.
  • human insulin As a first line drug for treating diabetes, human insulin has a short duration of action, which makes frequent injections necessary and cause extremely inconvenience to patients. Therefore, people are committed to obtaining some insulin analogs and derivatives thereof with a longer half-life and long term action on human body. Among them, the modification of human insulin or analogs thereof with acylated groups is an effective method to increase the half-life of insulin.
  • the applicant's patent application PCT/CN2017/095377 provides a human insulin analog with position B29 substituted with a long-chain fatty acid and amino acid at position B30 deleted, and discloses the structure and biological activity of the human insulin analog.
  • WO9507931 discloses an insulin (i.e.
  • WO2005012347 discloses a human insulin analog with B29 position substituted with a glutamic acid and a long-chain fatty acid and amino acid at position B30 deleted.
  • WO2007074133 discloses a preparation of the above insulin analogs, and LysB29 (N ⁇ -hexadecanodiacyl- ⁇ -glutamyl de(B30) human insulin (insulin degludec) preparation disclosed in the patent contains sodium chloride.
  • the liquid preparation containing sodium chloride can not only reduce the production of high molecular weight polymers, but also have no influence on the hypoglycemic effect of insulin.
  • the present invention provides a pharmaceutical composition comprising an acylated derivative of human insulin analog, wherein the acylated derivative of human insulin analog has a structure represented by the following general formula I: S-W-X-Y-Z (I)
  • W forms an amide bond with the ⁇ -amino group of the lysine residue of the B-chain.
  • n is an integer between 2 and 5, preferably 2.
  • Human insulin with threonine deletion at position 30 of the B chain is a human insulin analog, wherein the amino acid sequences of the A and B chains are as follows: A chain: GIVEQCCTSICSLYQLENYCN SEQ ID NO. 1 B chain: FVNQHLCGSHLVEALYLVCGERGFFYTPK SEQ ID NO.2.
  • the diamino compound containing a carboxylic acid group represented by X can be -HN(CH 2 )pCH(COOH)NH-, wherein p is an integer between 2 and 10, preferably an integer between 2 and 6, more preferably an integer between 2 and 4, most preferably 4.
  • -W-X-Y-Z has the following structure:
  • a particularly preferred acylated derivative of human insulin analog in the present invention can be customarily named as N ⁇ -(HOOC(CH 2 ) 14 CO)-N ⁇ -(OCCH 2 CH 2 CO-(N ⁇ B29 -Des(B30) human insulin))-Lys-OH or B29 (N ⁇ -(N ⁇ -hexadecanedioic acid-L-lysine-N ⁇ -oxobutanoyl)) Des(B30) human insulin, which has a specific structure of the following formula (Ia), more preferably, it has a structure of (Ib).
  • the acylated derivative of human insulin analog forms a complex with Zinc, which is a 6-mer of an acylated derivative of human insulin analog, wherein each 6-mer contains more than 4 zinc atoms, namely 6 molecules of acylated insulin contain more than 4 zinc atoms; more preferably 5 to 8 zinc atoms, particularly preferably 5 zinc atoms
  • the stabilizer is selected from but not limited to sodium chloride, and the concentration of sodium chloride is preferably 5-20 mM, more preferably 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13mM, 14mM, 15mM, 20mM, most preferably 10mM.
  • concentration of sodium chloride in the present invention refers to the concentration of sodium chloride in the final product.
  • the preservative is selected from but not limited to phenol and/or m-cresol;
  • the pH regulator is selected from acid and/or alkali, preferably but not limited to hydrochloric acid and/or sodium hydroxide;
  • the osmotic pressure regulator is selected from but not limited to glycerol and/or mannitol.
  • the zinc can be any zinc salt, preferably zinc acetate.
  • the composition comprises:
  • the content of the present invention refers to the mass (g) volume (100 mL) fraction of each component in the total volume of the composition according to the total volume of the composition, for example, content of 0.05% refers to the content of 0.05g substance in a 100 mL of solution, and so on for the contents of others.
  • the composition comprises: Lysine B29 (N ⁇ -(N ⁇ -hexadecanedioic acid-L-lysine-N ⁇ -oxobutanoyl)) Des(B30) human insulin 3.72mg; phenol 1.5mg; m-cresol 1.72mg; glycerol 19.6mg; sodium chlori de 0.58mg; zinc acetate 109.76 ⁇ g; sodium hydroxide; hydrochloric acid; make up to 1 ml with water for injection.
  • pH value is preferably 6-8, more preferably 7.4-7.8, most preferably 7.6.
  • the composition further comprises pharmaceutically acceptable carrier.
  • the composition may contain fast-acting insulin in addition to the acylated derivative of the above-mentioned human insulin analog.
  • the fast-acting insulin also known as ultra-short-acting insulin, has a short acting time after injection. It takes effect 10 to 15 minutes after subcutaneous injection, with a peak time of 1 to 2 hours and a duration of 4 to 6 hours.
  • Conventional fast-acting insulins in the art includes, e.g, insulin aspart (for example, NovoRapid) and insulin lispro (for example, Humalog).
  • the present invention also provides a method for preparing the pharmaceutical composition, which comprises a step of mixing an acylated derivative of insulin analog with any one or more selected from the group consisting of a stabilizer, a preservative, a pH regulator, an osmotic pressure regulator.
  • the invention also provides a use of the pharmaceutical composition in the preparation of a medicament for treating diabetes.
  • the specific dosage form of the pharmaceutical composition of the present invention does not need to be limited.
  • the present invention provides a method for treating diabetes, which comprises administering the pharmaceutical composition of the acylated derivative of human insulin analog to a patient in need of treatment.
  • the preservative and the bacteriostatic agent can have the same meaning.
  • X01 150 g, 524.5 mmol was added into dry THF (2.5 L) at room temperature, then catalytic amount of DMF (1.0 mL) was added, and oxalyl chloride (49 mL) was poured into a 100 mL constant pressure dropping funnel to slowly dropwise added into the reaction bottle. During about two hours of adding oxalyl chloride, gas was generated, which needs to be continuously deflated. After the dropwise addition was completed, the mixture was stirred at room temperature for 1.5 h, and then THF was spin-dried under reduced pressure. DCM (800 mL) and tert-butanol (500 mL) were added to the reaction flask and stirring was performed at room temperature overnight.
  • DCM 800 mL
  • tert-butanol 500 mL
  • X02 (28.5 g, 83.3 mmol) was dissolved in DCM (200 mL), N-hydroxysuccinimide (5.54 g, 48.1 mmol) and diisopropylcarbodiimide (7.6 mL) were added at room temperature. After stirring at room temperature for 1 day, TLC showed that the reaction was basically completed. Then the mixture was filtered to remove insoluble solids, the solvent was spin-dried under reduced pressure, and the mixture was purified by column chromatography to obtain 28.5 g of X04.
  • X11 (30.6 g, 46.3 mmol) was dissolved in absolute ethanol (200 mL), stirred at room temperature, and 6.0 g of 10% Pd/C was added. Then hydrogen gas was filled, and the mixture was stirred vigorously and reacted at room temperature overnight. The mixture was suction filtered with diatomite and washed with absolute ethanol three times, and the filtrate was spin-dried to obtain 24.5 g of crude X12, which was directly used in the next reaction.
  • X12 24 g, 45.6 mmol was dissolved in dry THF (200 mL), triethylamine (12.7 mL) was added, follow by cooling the temperature to 0 °C.
  • Succinic anhydride (5.2 g, 52 mmol) was added to the reaction system in batches, continuously stirred at 0 °C for 30 min, and then transferred to room temperature and stirred overnight.
  • the THF was spin-dried under reduced pressure, and the residue was dissolved in dichloromethane (500 mL), washed twice with 5% citric acid solution (500 mL ⁇ 2) and once with saturated brine, and dried over anhydrous sodium sulfate.
  • the solvent was spin-dried under reduced pressure to obtain 29.0 g of crude X13, which was directly used in the next reaction.
  • X14 (3.0 g, 4.1 mmol) was dissolved in trifluoroacetic acid (15 mL) and stirred at room temperature for 45 min. Then trifluoroacetic acid was spin-dried under reduced pressure at low temperature, anhydrous ether was added to obtain solid precipitates that was subsequently filtered. The filter cake was washed three times with anhydrous ether and the solid was dried to obtain 1.8 g of product X15.
  • Lysine B29 N ⁇ -(N ⁇ -hexadecanedioic acid-L-lysine-N ⁇ -oxobutanoyl)
  • Lysine B29 N ⁇ -(N ⁇ -hexadecanedioic acid-L-lysine-N ⁇ -oxobutanoyl)
  • the crude solution containing precursor was diluted with water to make the organic phase content about 15% (v:v), filtered with a 0.45 ⁇ m filter membrane and purified by RP-HPLC to obtain a purified solution.
  • the purified solution was replaced with water for injection using an ultrafiltration membrane package system and lyophilized to obtain 26 mg of lyophilized product.
  • the structural formula of the obtained molecule is as follows.
  • Lysine B29 N ⁇ -(N ⁇ -hexadecanedioic acid-L-lysine-N ⁇ -oxobutanoyl)
  • the target product was digested with V8 protease and LC-MS analysis of the enzymolytic product showed that a total of 4 peptide fragments were produced, with molecular weights of 416.23Da (A1-A4), 2968.29Da (A5-A17, B1-B13), 1376.57Da (A18-A21, B14-B21) and 1510.84Da (B22-B29), respectively, which are consistent with the theoretical molecular weight of peptide fragments.
  • the B22-B29 peptide fragment is a peptide fragment modified with fatty acid chain.
  • INS-C represents Lysine B29 (N ⁇ -(N ⁇ -hexadecanedioic acid-L-lysine-N ⁇ -oxobutanoyl)) Des(B30) human insulin in the embodiment.
  • the prescription of INS-C injection is as follows: Prescription composition Unit prescription 5000 bottles of prescription Function INS-C 3.72 mg 20.46 g basic remedy zinc acetate 109.76 ⁇ g 0.60 g stabilizer phenol 1.5 mg 8.25 g bacteriostatic agent m-cresol 1.72 mg 9.46 g bacteriostatic agent glycerol 1 19.6 mg 107.80 g 2 osmotic pressure regulator sodium chloride 0.58 mg 3.19 g stabilizer sodium hydroxide q.s. q.s. pH regulator hydrochloric acid q.s. q.s. pH regulator water for injection to 1 mL 5500 mL solvent Note: Molecular formula of zinc acetate: C 4 H 6 O 4 Zn•2H 2 O
  • the excipients were mixed with the prescribed amount of INS-C active pharmaceutical ingredient, the water for injection was supplemented to 90% of the target volume, the pH was adjusted to 7.4 ⁇ 7.8 with NaOH solution or HCl solution, the target pH was 7.6, then water for injection was added to the full amount, and the mixture were mixed well.
  • the mixture was filtered with 0.22 ⁇ m PVDF membrane, and the filtrate is filled in a 2 mL neutral borosilicate glass injection bottle according to a volume of 1.1 mL per bottle, with the filling volume of 1.05 mL to 1.15 mL.
  • Bottles were stoppered and capped. The filling volume is monitored during the filling process, and the integrity of the filter element was tested before and after filtration. Bottles were subjected to light inspection and then packaged.
  • INS-C represents Lysine B29 (N ⁇ -(N ⁇ -hexadecanedioic acid-L-lysine-N ⁇ -oxobutanoyl)) Des(B30) human insulin in the embodiment.
  • Prescription information is as follows: Prescription composition Concentration and pH of prescription Prescription 1 Prescription 2 Prescription 3 pH of prescription 7.2 7.2 7.2 INS-C (nmol/mL) 600 600 600 zinc acetate (nmol/mL) 500 500 500 glycerol (mg/mL) 19.6 19.6 19.6 phenol (mg/mL) 1.5 1.5 1.5 m-cresol (mg/mL) 1.72 1.72 1.72 sodium chloride (mg/mL) 0 10 20
  • Table 1 shows that sodium chloride can reduce the formation of high polymers as well as the formation of other impurities, thus improving the stability of active substances.
  • INS-C represents Lysine B29 (N ⁇ -(N ⁇ -hexadecanedioic acid-L-lysine-N ⁇ -oxobutanoyl)) Des(B30) human insulin in the embodiment.
  • the prescription information of INS-C injection and insulin degludec injection are as follows: Product Tresiba® N/A Function Common name/code name insulin degludec injection INS-C injection Specification 300 U /3mL (100 U/mL) 1m1:3.72mg (600nmol/ml) active ingredient insulin degludec INS-C basic remedy excipi ents glycerol 19.6mg/mL 19.6mg/mL osmotic pressure regulator phenol 1.50mg/mL 1.50mg/mL bacteriostatic agent m-cresol 1.72mg/mL 1.72mg/mL bacteriostatic agent Zinc 32.7 ⁇ g/mL 32.7 ⁇ g/mL stabilizer sodium chloride N/A 0.58 mg/mL stabilizer hydrochlori c acid q.s. q.s. pH regulator sodium hydroxide q.s. q.s. pH regulator solvent water for injection added to 3ml added to 1ml solvent
  • Insulin degludec injection and 3 batches of pilot test samples of INS-C injection were placed under accelerated test conditions at 25°C ⁇ 2°C, and samples were taken at 0, 1, 2, 3 and 6 months respectively for determination and each index was examined.
  • Insulin degludec injection and 3 batches of pilot test samples of INS-C injection were placed for long-term storage at a low temperature of 5°C ⁇ 3°C, and samples were taken at 3, 6, 9, 12, 18, 24 and 36 months respectively for measurement, sampling and measuring at regular intervals. The starting point for the investigation of insulin degludec injection was calculated based on its delivery time.
  • INS-C represents Lysine B29 (N ⁇ -(N ⁇ -hexadecanedioic acid-L-lysine-N ⁇ -oxobutanoyl)) Des(B30) human insulin in the embodiment.
  • test samples were stored in the dark at 4°C under a dosage of 7.5 nmol/kg. The temperature of the drugs was restored to room temperature when administered.
  • SPF rats were raised in the laboratory environment for 7 days with standard feed and standard cages at a temperature of 20-25 °C and a humidity of 40-60%. The day before modeling, the rats were fasted for 16 hours, injected STZ (65 mg/kg) intraperitoneally and resumed feeding one hour later. After modeling, sufficient drinking water (2-3 times the normal amount of drinking water was provided) and food were given daily, and litter was changed 1-2 times daily to kept dry. Fasting blood glucose was measured on the fifth day (fasting for 6 hours), and rats with a blood glucose value> 16.7 mmol/L were selected. These rats were randomly divided into 5 groups based on blood sugar levels.
  • Animal grouping and administration information are as follows: Groups Animal type Quantity of animals Administration dosage (nmol /kg) Administr ation volume (mL/kg) Administration route Administration frequency Control STZ rat 10 / 1 SC once insulin degludec injection STZ rat 10 7.5 1 SC once INS-C injection STZ rat 9 7.5 1 SC once
  • the basic blood glucose level of the control group was 26.6 mmol/L before administration, and gradually decreased after administration, reaching 10.1 mmol/L after 24 hours, with a blood glucose change value of 15.5 mmol/L.
  • the blood glucose change value of the insulin degludec positive drug group before and after administration was 20.1 mmol/L.
  • the blood glucose levels of the insulin degludec positive drug group were significantly different from that of the control group at 1, 2, 4, 6, 8, 10 and 12 hours after administration, indicating the effectiveness of the animal model and experimental method.
  • the test drug INS-C could significantly reduce the animals' blood glucose level within 24 hours after administration. From the perspective of blood glucose value, the blood glucose value of the test drug group 3.9 ⁇ 0.6 mmol/L) was lower than that of the control group (10.1 ⁇ 3.3 mmol/L) and also lower than that of insulin degludec (6.4 ⁇ 1.4 mmol/L), indicating that INS-C injection had a good long-term hypoglycemic effect.
  • Example 6 Investigation of the pharmacokinetic properties of sodium chloride-containing preparation, sodium chloride-free preparations and sodium chloride-containing preparation after being kept at room temperature for 20 hours in normal rats
  • Administration dosage nmol/kg
  • Administration volume mL/kg
  • Administration route Administration frequency 1 sodium chloride-free preparations 5 50 1 SC once 2 sodium chloride-containing preparations 5 50 1 SC once 3 sodium chloride-containing preparations after being kept at room temperature for 20 hours
  • the sodium chloride-free INS-C preparation 600 nmol/mL
  • sodium chloride-containing INS-C preparation 600 nmol/mL
  • Group 3 sodium chloride-containing INS-C preparation (600 nmol/mL) was kept in the dark and room temperature environment for 20 hours, then diluted to 50 nmol/mL with a blank solvent before administration, wherein the sodium chloride concentration in the sodium chloride group was 0.58 mg/mL.

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EP19747024.8A 2018-02-01 2019-01-31 Composition pharmaceutique comprenant un dérivé acylé d'analogue d'insuline humaine et son procédé de préparation Withdrawn EP3747896A4 (fr)

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WO2022111642A1 (fr) * 2020-11-27 2022-06-02 江苏恒瑞医药股份有限公司 Procédé de préparation d'un dérivé acylé d'insuline ou d'un analogue de celui-ci
KR20240013778A (ko) * 2021-05-24 2024-01-30 선샤인 레이크 파르마 컴퍼니 리미티드 신규한 아실화된 인슐린 유사체

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US20030072737A1 (en) * 2000-12-29 2003-04-17 Michael Brines Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs
PT1969004E (pt) * 2005-12-28 2011-11-25 Novo Nordisk As Composições que compreendem uma insulina acilada e zinco e método para criar tais composições
AU2011252127B2 (en) * 2010-05-10 2014-02-20 Novo Nordisk A/S Process for the preparation of insulin-zinc complexes
WO2013086927A1 (fr) * 2011-12-15 2013-06-20 上海恒瑞医药有限公司 Analogue d'insuline humaine et son dérivé acylé
US9856292B2 (en) * 2014-11-14 2018-01-02 Bristol-Myers Squibb Company Immunomodulators
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TW201934137A (zh) 2019-09-01
WO2019149245A1 (fr) 2019-08-08
EP3747896A4 (fr) 2021-11-24
CA3090199A1 (fr) 2019-08-08
CN111315766A (zh) 2020-06-19
US20210040171A1 (en) 2021-02-11
AU2019214159A1 (en) 2020-09-03
BR112020015457A2 (pt) 2020-12-08
JP2021512124A (ja) 2021-05-13
CN111315766B (zh) 2023-05-12
TWI740099B (zh) 2021-09-21

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